Genetics of congenital megacolon in East Asians

Abstract

Hirschsprung disease (HSCR), also known as congenital megacolon, is characterized by the absence of enteric ganglia in the hindgut. HSCR is a multigenic neurocristopathy with a two-fold increase in the incidence among East Asians. The major HSCR gene, RET, has both rare and common variants contribute to the disease risk. In particular, ~80% of Asian HSCR patients carry the high risk common enhancer allele. When in trans with the recently discovered, Asian-specific missense variant, the RET enhancer SNP increases the risk of HSCR by more than 20-fold. Thus far, over 10 HSCR genes were found to have common and/or rare variants attribute to disease susceptibility. To discover novel HSCR-associated gene(s), we performed a whole genome sequencing (WGS) of 443 HSCR cases and 493 controls of East Asian ethnicity. Rare variant association analysis was carried out and, with subsequent follow-up study, we identified a significant excess of rare protein-altering mutations in BACE2 (p=2.9x10-6) in HSCR cases (4%) compared with controls (0.6%). The relevance of BACE2 in HSCR is highlighted by the facts that i) the encoded protein has recently been proposed as a target for drug-based treatment of HSCR; and ii) BACE2 maps to the HSCR-Down Syndrome (DS) critical chromosomal region, with DS being the most frequent chromosomal abnormality associated with HSCR. The BACE2-HSCR association may represent the missing link between these two disorders. Results of the common variant association analysis will also be presented.